Saquinavir CYP3A4/5/7 substrate

Of aU the HIV protease inhibitors, saquinavir is the least potent inhibitor of CYP3A4. Nonetheless, it is recommended that the drug not be coadministered with ergot derivatives, triazolam, midazolam, or other CYP3A4 substrates with a low therapeutic index. Saquinavir clearance is increased with CYP3A4 induction thus coadministration of rifampin, nevirapine, or efavirenz lowers saquinavir concentrations and should be avoided. The effect of nevirapine or efavirenz on saquinavir may be partially or completely reversed with ritonavir. 

Cytochrome P-450 system.The metabolism of saquinavir is mediated by cytochrome P-450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp. 

Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate thus, there are many potential drug-drug interactions (Table 49-4). A decreased dose of saquinavir is recommended when -administered with nelfinavir. Increased saquinavir levels when -administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels may increase if co administered with saquinavir and should therefore be monitored. Liver function tests should be monitored if saquinavir is -administered with delavirdine or rifampin. There is no evidence of human teratogenicity from saquinavir there is short-term safety data for both mother and infant. 

Drug-drug transport interactions are important in combinationtherapy with HIV protease inhibitors (117). Many protease inhibitors are substrates for and inhibitors of CYP3A4 and P-gp. Different combination effects (e.g./ intrinsic clearance of amprenavir is reduced by nelfinavir and indinavir but not saquinavir) depend on the extent to which one or both of these enzymes are affected. 

Sildenafil is contraindicated in patients who are taking organic nitrates, for their metabolism is blocked and severe and acute hypotension result. Patients with recent stroke or myocardial infarction or whose blood pressure is known to be < 90/50 mmHg should not use it. Sildenafil is a substrate for the P450 isoenzyme CYP3A4 (and to a lesser extent CYP2C9) which gives scope for interaction with inhibitors or inducers of this system. The metabolic inhibitors erythromycin, saquinavir and ritonavir (protease inhibitors used for AIDS), and cimetidine, for example, produce substantial rises in the plasma concentration of sildenafil. 

Protease inhibitors are inhibitors and substrates of the eytochrome P450 isoenzyme CYP3A4, with ritonavir being the most potent inhibitor and saquinavir the least (see Antivirals , (p.772)). They probably interact by inhibiting each other s gut (pre-absorption) and hepatie (post-absorption) metabolism, so resulting in increased absorption and deereased elimination. A meehanism involving inhibition of P-glyeoprotein may also be involved. ... 

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